TY - JOUR
T1 - IDH1-mutant cancer cells are sensitive to cisplatin and an IDH1-mutant inhibitor counteracts this sensitivity
AU - Khurshed, Mohammed
AU - Aarnoudse, Niels
AU - Hulsbos, Renske
AU - Hira, Vashendriya V. V.
AU - van Laarhoven, Hanneke W. M.
AU - Wilmink, Johanna W.
AU - Molenaar, Remco J.
AU - van Noorden, Cornelis J. F.
PY - 2018
Y1 - 2018
N2 - Isocitrate dehydrogenase (IDH1)-1 ismutated in various types of human cancer, and the presence of this mutation is associatedwith improved responses to irradiationandchemotherapy in solid tumor cells.MutatedIDH1 (IDH1MUT) enzymes consume NADPH to produce D-2-hydroxyglutarate (D-2HG) resulting in the decreased reducing power needed for detoxification of reactive oxygen species (ROS), for example. The objective of the current studywas to investigate the mechanismbehind the chemosensitivity of thewidely usedanticancer agent cisplatinin IDH1MUT cancer cells.Oxidative stress,DNAdamage, andmitochondrial dysfunction caused by cisplatin treatment were monitored in IDH1MUT HCT116 colorectal cancer cells and U251 glioma cells. We found that exposure to cisplatin induced higher levels of ROS,DNAdouble-strand breaks (DSBs), and cell death in IDH1MUT cancer cells, as comparedwith IDH1 wild-type (IDH1WT) cells.Mechanistic investigations revealed that cisplatin treatment dose dependently reduced oxidative respiration in IDH1MUT cells, which was accompanied by disturbed mitochondrial proteostasis, indicative of impaired mitochondrial activity. These effectswere abolished by the IDH1MUT inhibitor AGI-5198 andwere restored by treatment with D-2HG.Thus, our study shows that altered oxidative stress responses anda vulnerable oxidativemetabolismunderlie the sensitivityof IDH1MUT cancer cells to cisplatin.-Khurshed,M., Aarnoudse, N.,Hulsbos, R., Hira,V. V. V., van Laarhoven,H.W.M.,Wilmink, J.W.,Molenaar, R. J., vanNoorden, C. J. F. IDH1-mutant cancer cells are sensitive to cisplatin and an IDH1-mutant inhibitor counteracts this sensitivity.
AB - Isocitrate dehydrogenase (IDH1)-1 ismutated in various types of human cancer, and the presence of this mutation is associatedwith improved responses to irradiationandchemotherapy in solid tumor cells.MutatedIDH1 (IDH1MUT) enzymes consume NADPH to produce D-2-hydroxyglutarate (D-2HG) resulting in the decreased reducing power needed for detoxification of reactive oxygen species (ROS), for example. The objective of the current studywas to investigate the mechanismbehind the chemosensitivity of thewidely usedanticancer agent cisplatinin IDH1MUT cancer cells.Oxidative stress,DNAdamage, andmitochondrial dysfunction caused by cisplatin treatment were monitored in IDH1MUT HCT116 colorectal cancer cells and U251 glioma cells. We found that exposure to cisplatin induced higher levels of ROS,DNAdouble-strand breaks (DSBs), and cell death in IDH1MUT cancer cells, as comparedwith IDH1 wild-type (IDH1WT) cells.Mechanistic investigations revealed that cisplatin treatment dose dependently reduced oxidative respiration in IDH1MUT cells, which was accompanied by disturbed mitochondrial proteostasis, indicative of impaired mitochondrial activity. These effectswere abolished by the IDH1MUT inhibitor AGI-5198 andwere restored by treatment with D-2HG.Thus, our study shows that altered oxidative stress responses anda vulnerable oxidativemetabolismunderlie the sensitivityof IDH1MUT cancer cells to cisplatin.-Khurshed,M., Aarnoudse, N.,Hulsbos, R., Hira,V. V. V., van Laarhoven,H.W.M.,Wilmink, J.W.,Molenaar, R. J., vanNoorden, C. J. F. IDH1-mutant cancer cells are sensitive to cisplatin and an IDH1-mutant inhibitor counteracts this sensitivity.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85055876687&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29879375
U2 - https://doi.org/10.1096/fj.201800547R
DO - https://doi.org/10.1096/fj.201800547R
M3 - Article
C2 - 29879375
SN - 0892-6638
VL - 32
SP - 6344
EP - 6352
JO - FASEB Journal
JF - FASEB Journal
IS - 11
ER -